PHILADELPHIA (January 9, 2024) — A new study by Fox Chase Cancer Center scientists has found a key immunological pathway involved in anaplastic large cell lymphoma (ALCL), an important step toward developing new therapies. Researchers also identified a potential drug to target the pathway.
The study adds significantly to what scientists know about two subtypes of this rare and aggressive lymphoma, including ALK positive, which can be treated with chemotherapy, and ALK negative, which has few treatment options. Anaplastic large cell lymphoma is a fast-growing cancer that occurs in T-cells, an important type of cell in the immune system.
“We wanted to gain a comprehensive molecular understanding of the ALCL pathology so that we can try to find novel therapeutic approaches,” said Yibin Yang, PhD, an Associate Professor in the Cancer Signaling and Microenvironment Research Program at Fox Chase. “We ended up identifying an unexpected pathway.”
For the study, researchers at Fox Chase and other institutions conducted genome-wide CRISPR library screenings for both subtypes of ALCL. They found that an immunological pathway called IL-1R played a key role in supporting the survival of ALK-negative ALCL cancer cells. This pathway is typically involved with the inflammatory process, Yang said.
When researchers took a closer look, they found that the IL-1R pathway is activated by a cytokine called IL-1, which is essential for the induction and maintenance of inflammatory responses that assist in the growth of tumors in ALCL cells and primary cases of ALCL lymphoma.
Yang said the finding was initially a surprise since, as a critical mediator of immunity and inflammation, the IL-1R signaling pathway has been shown to play an essential role in many solid tumors in response to increased IL-1 in the tumor microenvironment — the cells, molecules, and other structures surrounding the tumor.
In solid tumors, chronic inflammation could increase the tendency to develop tumors related to IL-1. However, such an inflammatory environment is usually rare in lymphoma, and its role in lymphoid malignancies has not been evaluated. But Yang said that after further consideration, the results made sense because primary cutaneous ALCL, which primarily affects the skin, exhibits the highest IL-1 production in primary cases. This observation raises the possible link between inflammatory skin conditions and the development of ALCL.
In a follow-up study, researchers found that pacritinib, an existing targeted therapy drug also known by its brand name Vonjo, was effective against ALK-negative ALCL in vitro and in a mouse model, supporting clinical evaluation for its use against ALCL. The result is exciting, Yang said, because the drug, which is a JAK2/IRAK1 dual inhibitor, is already approved by the Food and Drug Administration for a bone marrow disorder, which means it could be moved to clinical trials for ALCL more quickly.
Along with the findings about ALCL, the team’s discovery about the mechanism of the IL-1R pathway could be a crucial tool in developing combination therapies to prevent cytokine storms, a life-threatening hyperactivation of the inflammatory response that can be a side effect of some T-cell immunotherapies.
Yang’s research team is now working on follow-up studies looking at how the IL-1R pathway influences the cellular microenvironment to promote cancer growth. “We’re trying to understand how this innate immune signaling plays a role in immunotherapies.”
The research was supported by NIH R01 CA259188, R01 CA251674, a Scholar Award from the Leukemia & Lymphoma Society, and a grant from Gabrielle’s Angel Foundation and The Mark Foundation.
The study, “Analysis and Therapeutic Targeting of the IL-1R Pathway in Anaplastic Large Cell Lymphoma,” was published in Blood.